Neurosome/Astrosome Compositions and Methods of Use

Abstract

Disclosed are methods for the production and testing of formulated biomimetic nanoparticles. These particles can be utilized towards promoting neural health and connectivity, for example, after injury and in diseased states.

What is claimed is: 
     
         1 . A drug delivery composition comprising a population of biomimetic proteolipid nanovesicles composed of synthetic lipids, phospholipids, and/or cholesterol, enriched of one or more neuronal-derived membrane fragments, polypeptides, or biologically-active fragments or derivatives thereof, and surrounding an aqueous core. 
     
     
         2 . The drug delivery composition of  claim 1 , wherein the proteolipid nanovesicles comprise at least one astrocyte-derived protein or active fragment thereof, at least one neuronal-derived protein or active fragment thereof, or a combination thereof on their surface. 
     
     
         3 . The drug delivery composition of  claim 1 , further comprising at least one therapeutic agent, including, for example, a therapeutic drug, a chemotherapeutic, an antiangiogenic compound, an antibiotic, an analgesic, an anti-inflammatory agent, a neuromodulatory agent, a neurogenic protein, polypeptide, or peptide, such as MeCP2, a DNA molecule, an RNA molecule, an antibody, or any combination thereof. 
     
     
         4 . The drug delivery composition of  claim 3 , wherein the therapeutic agent is derived from a population of human pluripotent stem cells or a population of neurons isolated or derived from one or more human pluripotent stem cells (hPSC). 
     
     
         5 . The drug delivery composition of  claim 1 , further comprising at least one therapeutic agent selected from the group consisting of an immune-stimulating agent, a tumor growth inhibitor, a protein, a peptide, an RNA molecule, a DNA molecule, an siRNA molecule, a RNAi molecule, a ssRNA molecule, a growth factor, an enzyme inhibitor, a binding protein, a blocking peptide, and any combination thereof. 
     
     
         6 . The drug delivery composition of  claim 1 , wherein the proteolipid nanovesicles are adapted configured to release the at least one therapeutic agent in response to an external stimulus, in response to a change in the environment of the population of biomimetic proteolipid nanovesicles, or as a result of degradation of a population of astroparticles, neurosomes, plurisomes, or any combination thereof. 
     
     
         7 . The drug delivery composition of  claim 1 , wherein degradation of the population of biomimetic proteolipid nanovesicles, astroparticles, neurosomes, or plurisomes occurs via enzyme-facilitated biodegradation of one or more of the lipids, the phospholipids, or the cholesterol comprising them. 
     
     
         8 . The drug delivery composition of  claim 1 , wherein the neuron-derived membrane fragments comprise at least one cellular-targeting moiety. 
     
     
         9 . The drug delivery composition of  claim 8 , wherein the at least one cellular-targeting moiety is a neuronal cell-targeting moiety, a ligand, a ligand-binding moiety, a receptor, such as ICAM1 and L1CAM, a receptor-binding moiety, an antibody or an antigen-binding fragment thereof, and any combination thereof. 
     
     
         10 . The drug delivery composition of  claim 9 , wherein the at least a first cellular-targeting moiety comprises a plurality of distinct antigenic ligands that elicit one or more target-specific immune responses in a mammalian host cell that is contacted with the population of nanovesicles. 
     
     
         11 . The drug delivery composition of  claim 1 , further comprising a diagnostic agent or a theranostic agent, or a combination thereof. 
     
     
         12 . The drug delivery composition of  claim 1 , comprising a diagnostic reagent selected from the group consisting of an imaging agent, a contrast agent, a fluorescent label, a radiolabel, a magnetic resonance imaging label, a spin label, and any combination thereof. 
     
     
         13 . The drug delivery composition of  claim 1 , comprising a chemically-targeting moiety that is disposed on the surface of the proteolipid nanovesicles, and that comprises a ligand, a dendrimer, an oligomer, an aptamer, a binding protein, an antibody, an antigen-binding fragment thereof, a biomolecule, or any combination thereof. 
     
     
         14 . The drug delivery composition of  claim 1 , wherein the neurosome- or astrosome-specific nanovesicles are about 100 to about 1000 nm in average diameter. 
     
     
         15 . The drug delivery composition of  claim 1 , wherein the synthetic phospholipids are selected from the group consisting of phosphatidylcholine, egg phosphatidic acid, D-Lin-MC3-DMA, 1,2-dioleoyl-sn-glycerophosphocholine (DOPC), 1,2-dioleoyl-sn-glycerophosphoethanolamine (DOPE), 1,2-dipalmitoyl-sn-glycerophosphocholine (DPPC), 1,2-distearoyl-sn-glycerophosphocholine (DSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (ammonium salt) (PEG-2000), 1,2-dipalmitoyl-3-dimethylammonium-propane (16:0 DAP), cholesterol, and any combination thereof. 
     
     
         16 . The drug delivery composition of  claim 1 , wherein the lipid-to-protein ratio is from about 160 to 5 (wt./wt.) to about 300:1. 
     
     
         17 . A population of isolated mammalian cells comprising the drug delivery composition of  claim 1 . 
     
     
         18 . A pharmaceutical formulation comprising the drug delivery composition of  claim 1 , and a pharmaceutically-acceptable buffer, diluent, excipient, or vehicle. 
     
     
         19 . A kit comprising the pharmaceutical formulation of  claim 18 , and instructions for administering the composition to a mammal in need thereof, as part of a regimen for the prevention, diagnosis, treatment, or amelioration of one or more symptoms of a neural disease, a brain dysfunction, an abnormal brain condition, or a brain trauma or injury in the mammal. 
     
     
         20 . A method for providing one or more neuroactive agents to a population of neural cells or a brain tissue within the body of an animal, comprising administering to the animal an amount of the pharmaceutical formulation of  claim 18 , for a time effective to provide the one or more neuroactive agents to the population of neural cells or brain tissue within the body of the animal. 
     
     
         21 . A method of administering a diagnostic, therapeutic, or prophylactic agent to one or more neural cells, tissues, organs, or systems of a mammalian subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical formulation of  claim 18 . 
     
     
         22 . The method of  claim 21 , wherein the therapeutic agent comprises at least a first siRNA, DNA, ssRNA, RNAi, or any combination thereof. 
     
     
         23 . The method of  claim 22 , wherein the therapeutic agent further comprises at least a first neurotherapeutic agent.